title: Extracellular protons inhibit charge immobilization in the cardiac voltage-gated sodium channel.
abstract: Low pH depolarizes the voltage-dependence of cardiac voltage-gated sodium (NaV1.5) channel activation and fast inactivation and destabilizes the fast-inactivated state. The molecular basis for these changes in protein behavior has not been reported. We hypothesized that changes in the kinetics of voltage sensor movement may destabilize the fast-inactivated state in NaV1.5. To test this idea, we recorded NaV1.5 gating currents in Xenopus oocytes using a cut-open voltage-clamp with extracellular solution titrated to either pH 7.4 or pH 6.0. Reducing extracellular pH significantly depolarized the voltage-dependence of both the QON/V and QOFF/V curves, and reduced the total charge immobilized during depolarization. We conclude that destabilized fast-inactivation and reduced charge immobilization in NaV1.5 at low pH are functionally related effects.
authors.affiliation: Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada.
authors.forename: D K
authors.initials: DK
authors.lastname: Jones
authors.forename: T W
authors.initials: TW
authors.lastname: Claydon
authors.forename: P C
authors.initials: PC
authors.lastname: Ruben
mesh_terms: D000818:Animals; D004553:Electric Conductivity; D004583:Electrons; D005110:Extracellular Space / Q000378:metabolism*; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015640:Ion Channel Gating; D007700:Kinetics; D009206:Myocardium / Q000378:metabolism*; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000737:chemistry / Q000378:metabolism*; D011522:Protons
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; D011522:Protons; C568320:SCN5A protein, human